EP0608111B1 - Isolation and structure of spongistatin 1 and its use as an anti-tumor agent - Google Patents
Isolation and structure of spongistatin 1 and its use as an anti-tumor agent Download PDFInfo
- Publication number
- EP0608111B1 EP0608111B1 EP94300362A EP94300362A EP0608111B1 EP 0608111 B1 EP0608111 B1 EP 0608111B1 EP 94300362 A EP94300362 A EP 94300362A EP 94300362 A EP94300362 A EP 94300362A EP 0608111 B1 EP0608111 B1 EP 0608111B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- brs
- brd
- spongistatin
- brt
- ddd
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 0 CC(C)C(C)CCC(C(C)COC(CC(CCC1)OC1(C1)*CCC1(C)O)=O)C1IC1I Chemical compound CC(C)C(C)CCC(C(C)COC(CC(CCC1)OC1(C1)*CCC1(C)O)=O)C1IC1I 0.000 description 2
- VGYXASMNJJBLBF-KTKRTIGZSA-N CCCC/C=C\C(CC(CC)C1)OC1(CC)N Chemical compound CCCC/C=C\C(CC(CC)C1)OC1(CC)N VGYXASMNJJBLBF-KTKRTIGZSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/181—Heterocyclic compounds containing oxygen atoms as the only ring heteroatoms in the condensed system, e.g. Salinomycin, Septamycin
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/44—Preparation of O-glycosides, e.g. glucosides
- C12P19/445—The saccharide radical is condensed with a heterocyclic radical, e.g. everninomycin, papulacandin
Definitions
- the present invention relates to the discovery and isolation of new and extremely potent constituent of an Eastern Indian Ocean marine sponge of the genes Spongia herein denominated "spongistatin 1".
- This new perhydropyran-containing structure was found to be remarkably potent and specific against twenty human cancer cell lines in the U.S. National Cancer Institute's panel.
- NCI National Cancer Institute
- J. Org. Chem. (1993) 58, 1302-1304 was published after the priority date of the present application. It relates to the isolation and structure of spongistatin 1 from an Eastern Indian Ocean Sponge.
- EP-A-0,264,173 (Arizona Board of Regents) relates to several Bryostatins isolated from Bugula neritina which exhibit potent antineoplastic activity.
- Spongistatin 1 has the following structure:
- the principal object of the present invention is the isolation of a structurally unprecedented macrocyclic lactone herein denominated "spongistatin 1" having a log molar TGI 50 of about ⁇ -10 against various human cancer cell lines.
- Another object of the present invention is the structural elucidation of the substance denominated "spongistatin 1".
- Spongistatin 1 was found to be incredibly active and selective against twenty (CCRF-CEM, HL-60, SR leukemias; NCI-H226, NCI H23, NCI H460, NCI H522 non-small cell lung; DMS 114, and 273 small cell lung; Colo 205, DCC-2998, HCT-116, RT29, KM 2022 colon; SF-239.
- U-251 CNS; SK-MEL-5 melanoma; OVCAR-3 and -8 ovarian; and A-498 renal cancers of the NCI panel of sixty human cancer cell lines with log molar TGI 50 ranging from -8.98 to ⁇ -10.00.
Abstract
Description
NMR assignments for spongistatin 1 recorded in CD3CN. Coupling constants are in Hz (in parenthesis). The mixing time for the HMBC was set at 130 microsecond). | |||
13C(100 MHz) | XHCorr. (400 MHz) | HMBC(500 MHz, C to H) | |
1 | 173.07 | H-2;H-41 | |
2 | 40.86 | 2.44 dd(10,18) | H-4 |
2.53 dd(2,18) | |||
3 | 63.59 | 4.25 brt(10) | H-2;H-8 |
4 | 34.65 | 1.55*;1.68 | H-2;H-6 |
5 | 67.06 | 4.92 brs | |
6 | 38.17 | 1.67 dd(5,14); | H-5;H-8 |
1.78 brd(14) | |||
7 | 99.26 | H-6;H-8;H-9a | |
8 | 46.76 | 1.47 d(14);1.60 | H-9a;H-6 |
9 | 69.64 | H-9a;OH(C9) ;H-8 | |
9a | 30.21 | 1.06 s | H-8;H-10 |
10 | 44.96 | 1.28 ;1.55 | H-9a;H-12;H-8 |
11 | 65.00 | 4.25 brt(10) | H-12;H-13a;H-15;H-6 |
12 | 44.24 | 1.99*;2.27 brd(14) | H-10;H-13a |
13 | 148.03 | H-12;H-13a;H-14a; | |
H-15 | |||
13a | 114.86 | 4.83 brs;4.83 brs | H-12;H-14 |
14 | 36.60 | 2.78 | H-13a;H-14a;H-15; |
H-16;H-12 | |||
14a | 12.09 | 1.04 d(6.9) | H-15 |
15 | 75.34 | 5.12 dd(1.7,11) | H-13a;H-14a;H-16; |
H-16a | |||
16 | 47.62 | 3.04 dq(7,11) | H-15;H-16a |
16a | 13.73 | 1.15 d(7) | H-15;H-16 |
17 | 213.52 | H-16;H-16a;H-18; | |
H-15 | |||
18 | 51.94 | 2.62 brd(18) | H-16;H-20 |
2.86 dd(11,18) | |||
19 | 66.16 | 4.00 brt(11) | H-18 |
20 | 37.70 | 0.97 ddd(12,12,12); | H-18;H-22 |
1.98 | |||
21 | 73.98 | 3.46 tt(4,4,12,12) | H-22;H-OMe;H-20 |
22 | 44.18 | 1.08 t(12);1.99 | H-21;H-20 |
23 | 99.91 | H-18;H-22;H-24;H-27 | |
24 | 34.91 | 1.55 ;2.28 | H-22 |
25 | 64.41 | 3.93 brm | H-26;H-27;H-24 |
26 | 39.11 | 1.57 ;1.57 | H-28;H-24 |
27 | 61.22 | 5.00 ddd(4.3,10,10) | H-26;H-29 |
28 | 131.22 | 5.32 brt(10) | H-27;H-30 |
29 | 133.42 | 5.48 ddd(10,10,10) | H-27;H-30 |
30 | 28.07 | 2.00 ;2.19 | H-28;H-29;H-31; |
H-32 | |||
31 | 27.04 | 1.23 ;1.60 | H-29;H-33;H-30;H-32 |
32 | 32.82 | 1.30 m;1.42 m | H-33 |
33 | 67.15 | 4.13 dt(3.4,3.4,8) | H-34a |
34 | 39.32 | 1.57 m | H-34a;H-36 |
34a | 11.55 | 0.81 d(7) | H-33;H-34 |
35 | 71.47 | 3.65 brs | H-34a;H-33;H-36 |
36 | 33.79 | 1.61 ;1.89 | OH(C37);H-34 |
37 | 99.41 | H - 3 3 ; H - 3 6 ; | |
OH(C37),H-38 | |||
38 | 73.11 | 3.34 brs | H-36 |
39 | 81.30 | 3.72 brd(10) | H-40a;H-41 |
40 | 37.26 | 1.91 | H-40a;H-39;H-41 |
40a | 12.69 | 0.74 d(7) | H-40;H-41 |
41 | 80.60 | 4.75 dd(9,11) | H-40a;H-39;H-40; |
H-42;H-43 | |||
42 | 73.11 | 3.12 t(9) | H-40;H-41;H-43; |
H-40a | |||
43 | 78.72 | 3.39 brt(9) | H-39;H-41;H-42;H-44 |
44 | 40.24 | 2.08 ;2.76 brd(13) | H-42;H-46;H-45a |
45 | 144.00 | H-45a;H-43;H-44; | |
H-46;H-47 | |||
45a | 116.61 | 4.86 brs;4.89 brs | H-44;H-46 |
46 | 43.93 | 2.33 brdd(7,14); | H-44;H-45a |
2.19 | |||
47 | 70.13 | 4.36 ddd(6,7,11) | H-46;H-48 |
48 | 139.21 | 6.11 dd(6,15) | H-46;H-47 |
49 | 126.99 | 6.41 brd(15) | H-47;H-48;H-51 |
50 | 139.21 | H-48;H-49;H-51 | |
51 | 116.48 | 5.35 brs;5.45 brs | H-48;H-49 |
OMe | 55.72 | 3.24 s | H-21 |
OAc | 21.78 | 1.94 s | |
171.61 | H-OAc(δ1.94);H-5 | ||
OAc | 21.00 | 1.84 s | |
170.21 | H-OAc(δ1.84);H-15 | ||
OH(C25) | 4.39 d(9.9) | ||
OH(C37) | 4.73 d(2) | ||
OH(C9) | 4.32 brs | ||
OH | 3.83 brm |
Claims (5)
- A compound according to claim 1 and having, when recorded in CD3CD, the NMR assignments;
13C(100 MHz) XHCorr.(400 MHz) HMBC(500 MHz, C to H) 1 173.07 H-2;H-41 2 40.86 2.44 dd(10,18) H-4 2.53 dd(2,18) 3 63.59 4.25 brt(10) H-2;H-8 4 34.65 1.55 ;1.68 H-2;H-6 5 67.06 4.92 brs 6 38.17 1.67 dd(5,14); H-5;H-8 1.78 brd(14) 7 99.26 H-6;H-8;H-9a 8 46.76 1.47 d(14);1.60 H-9a;H-6 9 69.64 H-9a;OH(C9);H-8 9a 30.21 1.06 s H-8;H-10 10 44.96 1.28*;1.55 H-9a;H-12;H-8 11 65.00 4.25 brt(10) H-12;H-13a;H-15;H-6 12 44.24 1.99*;2.27 brd(14) H-10;H-13a 13 148.03 H-12;H-13a;H-14a; H-15 13a 114.86 4.83 brs;4.83 brs H-12;H-14 14 36.60 2.78 H-13a;H-14a;H-15; H-16;H-12 14a 12.09 1.04 d(6.9) H-15 15 75.34 5.12 dd(1.7,11) H-13a;H-14a;H-16; H-16a 16 47.62 3.04 dq(7,11) H-15;H-16a 16a 13.73 1.15 d(7) H-15;H-16 17 213.52 H-16;H-16a;H-18; H-15 18 51.94 2.62 brd(18) H-16;H-20 2.86 dd(11,18) 19 66.16 4.00 brt(11) H-18 20 37.70 0.97 ddd(12,12,12); H-18;H-22 1.98 21 73.98 3.46 tt(4,4,12,12) H-22;H-OMe;H-20 22 44.18 1.08 t(12);1.99 H-21;H-20 23 99.91 H-18;H-22;H-24; H-27 24 34.91 1.55 ;2.28 H-22 25 64.41 3.93 brm H-26;H-27;H-24 26 39.11 1.57*;1.57 H-28;H-24 27 61.22 5.00 ddd(4.3,10,10) H-26;H-29 28 131.22 5.32 brt(10) H-27;H-30 29 133.42 5.48 ddd(10,10,10) H-27;H-30 30 28.07 2.00 ;2.19 H-28;H-29;H-31; H-32 31 27.04 1.23 ;1.60 H-29;H-33;H-30;H-32 32 32.82 1.30 m;1.42 m H-33 33 67.15 4.13 dt(3.4,3.4,8) H-34a 34 39.32 1.57 m H-34a;H-36 34a 11.55 0.81 d(7) H-33;H-34 35 71.47 3.65 brs H-34a;H-33;H-36 36 33.79 1.61 ;1.89 OH(C37) ;H-34 37 99.41 H-33;H-36;OH (C37),H-38 38 73.11 3.34 brs H-36 39 81.30 3.72 brd(10) H-40a;H-41 40 37.26 1.91 H-40a;H-39;H-41 40a 12.69 0.74 d(7) H-40;H-41 41 80.60 4.75 dd(9,11) H-40a;H-39;H-40; H-42;H-43 42 73.11 3.12 t(9) H-40;H-41;H-43; H-40a 43 78.72 3.39 brt(9) H-39;H-41;H-42;H-44 44 40.24 2.08 ;2.76 brd(13) H-42;H-46;H-45a 45 144.00 H-45a;H-43;H-44; H-46;H-47 45a 116.61 4.86 brs;4.89 brs H-44;H-46 46 43.93 2.33 brdd(7,14); H-44;H-45a 2.19 47 70.13 4.36 ddd(6,7,11) H-46;H-48 48 139.21 6.11 dd(6,15) H-46;H-47 49 126.99 6.41 brd(15) H-47;H-48;H-51 50 139.21 H-48;H-49;H-51 51 116.48 5.35 brs;5.45 brs H-48;H-49 OMe 55.72 3.24 s H-21 OAc 21.78 1.94 s 171.61 H-OAc(δ1.94);H-5 OAc 21.00 1.84 s 170.21 H-OAc(δ1.84);H-15 OH(C25) 4.39 d(9.9) OH(C37) 4.73 d(2) OH(C9) 4.32 brs OH 3.83 brm - A method for inhibiting the growth of human cancer cells which comprises administering to an in vitro environment containing such human cancer cells a pharmaceutically acceptable carrier combined with the compound of claim 1 in an amount effective to inhibit the growth of such human cancer cells in said environment.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/006,270 US5436400A (en) | 1993-01-19 | 1993-01-19 | Isolation and structure of spongistatin 1 |
US6270 | 1995-11-07 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0608111A1 EP0608111A1 (en) | 1994-07-27 |
EP0608111B1 true EP0608111B1 (en) | 1998-05-27 |
Family
ID=21720096
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP94300362A Expired - Lifetime EP0608111B1 (en) | 1993-01-19 | 1994-01-19 | Isolation and structure of spongistatin 1 and its use as an anti-tumor agent |
Country Status (8)
Country | Link |
---|---|
US (1) | US5436400A (en) |
EP (1) | EP0608111B1 (en) |
JP (1) | JPH072866A (en) |
AT (1) | ATE166652T1 (en) |
CA (1) | CA2113656C (en) |
DE (1) | DE69410492T2 (en) |
DK (1) | DK0608111T3 (en) |
ES (1) | ES2119077T3 (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5393897A (en) * | 1993-07-02 | 1995-02-28 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Isolation and structure of spongistatins 5,7,8 and 9 |
WO1997048278A1 (en) * | 1996-06-18 | 1997-12-24 | Arizona Board Of Regents, A Body Corporate Of The State Of Arizona Acting For And On Behalf Of The Arizona State University | Antifungal activity of the spongistatins |
US5883120A (en) * | 1997-06-16 | 1999-03-16 | Arizona Board Of Regents, A Body Corporate, Acting On Behalf Of Arizona State University | Antifungal activity of the spongistatins |
US5952376A (en) * | 1997-11-07 | 1999-09-14 | The Trustees Of The University Of Pennsylvania | Trienyl compounds |
US6521661B1 (en) | 2000-07-20 | 2003-02-18 | Harbor Branch Oceanographic Institution, Inc. | Cyclic peroxides as novel antifungal agents |
WO2016130969A1 (en) | 2015-02-13 | 2016-08-18 | George Robert Pettit | Silstatin compounds |
US11629167B2 (en) | 2017-11-09 | 2023-04-18 | Arizona Board Of Regents On Behalf Of Arizona State University | Betulastatin compounds |
CN114605430B (en) * | 2022-03-18 | 2023-09-05 | 中国科学院海洋研究所 | Macrocyclic dilactone compound, and preparation method and application thereof |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4833257A (en) * | 1986-07-28 | 1989-05-23 | Arizona Board Of Regents | Compositions of matter and methods of using same |
US5196447A (en) * | 1991-08-08 | 1993-03-23 | Arizona Board Of Regents, A Body Corporate Of The State Of Arizona, Acting On Behalf Of Arizona State University | Neristatin 1 |
-
1993
- 1993-01-19 US US08/006,270 patent/US5436400A/en not_active Expired - Fee Related
-
1994
- 1994-01-17 JP JP6030762A patent/JPH072866A/en active Pending
- 1994-01-18 CA CA002113656A patent/CA2113656C/en not_active Expired - Fee Related
- 1994-01-19 DK DK94300362T patent/DK0608111T3/en active
- 1994-01-19 AT AT94300362T patent/ATE166652T1/en not_active IP Right Cessation
- 1994-01-19 DE DE69410492T patent/DE69410492T2/en not_active Expired - Fee Related
- 1994-01-19 ES ES94300362T patent/ES2119077T3/en not_active Expired - Lifetime
- 1994-01-19 EP EP94300362A patent/EP0608111B1/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
ATE166652T1 (en) | 1998-06-15 |
CA2113656A1 (en) | 1994-07-20 |
CA2113656C (en) | 2000-07-18 |
DE69410492T2 (en) | 1998-11-05 |
ES2119077T3 (en) | 1998-10-01 |
JPH072866A (en) | 1995-01-06 |
DK0608111T3 (en) | 1999-01-18 |
EP0608111A1 (en) | 1994-07-27 |
DE69410492D1 (en) | 1998-07-02 |
US5436400A (en) | 1995-07-25 |
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